The present invention relates to novel therapeutic uses of a known compound, gabapentin, its derivatives, and pharmaceutically acceptable salts. The present invention concerns a method for treating physiological conditions associated with the use, or sequelae of use, of cocaine or other addictive drugs/substances in a mammal in need of such treatment.
Cocaine abuse and addiction have increased greatly during the last decade. Cocaine is a member of the class of drugs known as psychomotor stimulants. The term xe2x80x9cpsychomotor stimulantsxe2x80x9d refers to a class of drugs that stimulates a mammal""s central nervous system. Examples of psychomotor stimulants include, but are not limited to amphetamine, methamphetamine, methylphenidate, and other agents with similar pharmacological actions.
Often the use, or sequelae of use, of cocaine or other psychomotor stimulants is associated with psychopathological conditions. The psychopathological conditions of cocaine and other psychomotor stimulants are generally similar, or in some cases identical. Craving, dysphoria, and depression are important components of withdrawal syndromes from cocaine and psychomotor stimulants other than cocaine.
In animals, repeated exposure to cocaine can induce supersensitivity to many of its effects including seizures, behavioral hyperactivity, and stereotypy. The development of supersensitivity to the convulsant effects of cocaine following repeated exposures is similar in some respects to the phenomenon known as kindling, the reduction of seizure threshold after repeated electrical stimulation of certain brain regions. The brain regions in which kindling is obtained include portions of the limbic system, areas of the brain believed to be involved in normal emotional behaviors, as well as some psychopathological behaviors (eg, Post et al, 1972). Thus, it has been suggested that a kindling-like phenomenon may be involved in the development of cocaine addiction and craving.
U.S. Pat. No. 4,024,175, its divisional U.S. Pat. No. 4,087,544, and U.S. Pat. No. 5,563,175 cover the compounds of the instant invention, methods for preparing them, and several uses thereof. The uses disclosed are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients.
U.S. Pat. Nos. 5,025,035 and 5,084,479 also disclose methods for using the compounds of the instant invention. U.S. Pat. No. 5,025,035 discloses methods of treating depression. U.S. Pat. No. 5,084,479 discloses methods for treating neurodegenerative diseases. The patents are hereby incorporated by reference.
There is no disclosure in the above references to suggest the present invention""s uses of compounds of U.S. Pat. No. 4,024,175, its divisional U.S. Pat. No. 4,087,544, and U.S. Pat. No. 5,563,175 to treat physiological conditions associated with the use, or sequelae of use, of cocaine or other addictive agents.
To the extent that kindling-like phenomena are involved, it has been discovered that gabapentin, its derivatives and pharmaceutically acceptable salts, will be effective in treating not only seizures, but also physiological abnormalities or toxicities caused by repeated exposure to cocaine and/or other psychomotor stimulants.
It has also been discovered that gabapentin, its derivatives, and pharmaceutically acceptable salts will be effective in treating physiological conditions caused by repeated exposure to addictive drugs/substances other than cocaine.
There have been various reports that provide functional and neurochemical evidence that there are specific neurobiological commonalties between addictive drugs/substances. Dopamine neurotransmission in the mesolimbic system, and particularly in the nucleus accumbens, is currently recognized as a critical target of drugs of abuse (Wise R. A. and Bozarth M. A., Psychol Rev.,1987;94:469-492; Koob G. F., Trends Pharmacol. Sci., 1992; 13:177-184; Di Chiara G., Drug Alcohol Depend., 1995;38:95-121). Among drugs active in the central nervous system, the ability to act as a rewarding stimulus, to activate motor behavior, and to increase synaptic dopamine concentrations in the mesolimbic system are in some way linked. Drugs that are abused are from diverse classes (depressants, stimulants, nicotine, opiates, heroin, barbiturates, hallucinogens, sedative/hypnotics, solvents, steroids) suggesting that they might act through a common mediator. It has been determined that drugs abused by humans stimulate dopamine transmission in the nucleus accumbens while drugs with aversive properties reduced dopamine release and drugs not abused by humans failed to modify synaptic dopamine concentrations (Di Chiara G. and Imperato A., Proc. Natl. Acad. Sci., 1988;85:5274-5278). It has been discovered that successful treatment of a psychostimulant-induced physiological condition with gabapentin, its derivatives, and pharmaceutically acceptable salts can be extended to treating the physiological conditions of drugs of abuse other than cocaine and other psychomotor stimulants.
In one embodiment, the present invention discloses a method for treating physiological conditions associated with the use, or sequelae of use, of psychomotor stimulants such as cocaine and other abused drugs/substances. The present invention comprises administering a therapeutically effective amount of a compound of Formula I: 
wherein R1 is hydrogen or a lower alkyl and n is 4, 5, or 6 or a pharmaceutically acceptable salt thereof, in unit dosage form, to a mammal in need of said treatment. Preferably, it has been found that the administration of gabapentin is effective in treating physiological conditions associated with the use, or sequelae of use, of psychomotor stimulants and other addictive drugs/substances.
In another preferred embodiment, the present invention comprises administering a therapeutically effective amount of a compound of Formula II: 
wherein R11 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R12 is hydrogen or methyl; and R13 is hydrogen, methyl, or carboxyl; or an individual enantiomeric isomer thereof; or a pharmaceutically acceptable salt thereof, in unit dosage form, to a mammal in need of said treatment. Preferably, it has been found that the administration of pregabalin((S)-3-(aminoethyl)-5-methylhexanoic acid) is effective in treating physiological conditions associated with the use, or sequelae of use, of psychomotor stimulants and other addictive drugs/substances.
The term xe2x80x9cphysiological conditionsxe2x80x9d associated with the use, or sequelae of use, of psychomotor stimulants or other addictive drugs/substances is meant to cover a broad number of pathological states. Nonlimiting examples of pathological states include tachycardia, hypertension, mydriasis and agitation, death may be caused by a cardiovascular collapse or respiratory failure, viral hepatitis intracranial hemorrhages, cardiac arrhythmias secondary to hypertension, necrotizing angitits, fever, leukemoid reaction, disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. A number of other pathophysiological conditions that can be treated by the methods of the present invention are referenced in xe2x80x9cThe Pathology of Drug Abusexe2x80x9d, Steven B. Karch, 1993, CRC Press, Inc.
The term xe2x80x9caddictive drugs/substancesxe2x80x9d is meant to cover drugs/substances other than psychomotor stimulants that are abused, and preferably those drugs/substances that target dopamine neurotransmission. Addictive drugs/substances include but are not limited to depressants, nicotine, opiates, heroin, barbiturates, hallucinogens, sedative/hypnotics, solvents, steroids. Specific non-limiting examples of addictive drugs/substances include alfentanyl, alphaprodine, anileridine, bezitramide, codeine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, morphine, neperidine, phenomorphan, phenoperidine, piritradide, pholcodine, proheptazoine, properidine, propiran, racemoramide, thebacon, trimeperidine, and the pharmaceutically acceptable salts thereof.